Second generation anti-psychotics (SGAs) are widely prescribed to treat psychiatric disorders in adults and children and are among the 10 top selling medications world-wide. The pharmacology of SGAs is complex: they potently antagonize multiple G protein coupled receptors (GPCRs) including dopamine, serotonin, alpha- adrenergic and histamine receptors. Side effects of SGAs include increased incidence of obesity and type 2 diabetes among both acute and chronic users. Recent evidence indicates that SGAs are also associated with increased fracture risk and reduced bone mineral density; however the underlying molecular and pharmacological mechanisms leading to these severe endocrine side effects are unknown. Children and adolescents are the most susceptible to metabolic side effects, and in this proposal we hypothesize, that the skeleton is also vulnerable during the time of peak bone accrual. Thus the over-arching goal of this proposal is to elucidate the cellular/pharmacological mechanisms underlying SGA-induced bone loss, using the most widely prescribed, SGA, risperidone (RIS). Our novel central hypothesis is that RIS therapy is associated with significant bone loss, and this adverse side effect occurs via multiple mechanisms: 1) by directly interacting with bone cells and uncoupling bone remodeling; [2) via hyper-prolactinemia induced hypogonadism] and 3) by modulating the sympathetic nervous system output to bone. The goals of this project are to 1) determine whether SGAs have direct effects on osteoclast and osteoblast biology; 2) to examine the effect of RIS treatment in vivo on the skeletal-energy metabolism network, 3) determine if effects are mediated, at least in part by the sympathetic nervous system (SNS) and/or hypogonadism; and 4) to determine if detrimental effects of RIS on bone can be ameliorated with mechanism-directed co-therapy. To achieve these goals we will employ a pharmacologic approach to explore the functional consequence of specific receptor binding effects of RIS, and prolactin-sparing SGAs olanzapine and clozapine, using osteoblast and osteoclast culture in vitro, and in vivo by using established mouse models of RIS-induced bone loss. We will also explore whether -blocker or bisphosphonate co-therapy can alter adverse effects of RIS on bone and energy metabolism. Finally, an important part of our strategy involves continuous monitoring of drug exposure (RIS and its active metabolite, 9-OH RIS) in plasma and bone marrow in order to gain understanding of the pharmacokinetic/pharmacodynamic relationships associated with adverse endocrine side effects of RIS therapy. These studies are both innovative and collaborative, capitalizing on the complementary strengths (pharmacology, drug metabolism, endocrinology, bone biology, diabetes, and neuroscience) of our interdisciplinary research team. Results of these novel mechanistic pharmacology studies may help inform public health policy concerning SGA prescribing and patient monitoring practices and may help inform strategies for prescribing co-therapies in order to minimize side effects in vulnerable patient populations.